Determination of the antioxidative activity of substituted 5-aminopyrimidines

The aminopyrimidine structural motif can be found in diverse biologically active compounds. This study aimed to describe the antioxidant activity of a series of di- and tri-substituted 5-aminopyrimidines using in vitro (TEAC, LPO) and cell-based assays. 2,4,6-trisubstituted 5-aminopyrimidines displayed the highest activity in the TEAC and LPO assays whereas compounds with protected 5-aminogroup were active in the cellular assay. This is most likely because of their better membrane permeability and intracellular metabolic activation. In summary, we have identified the antioxidant activity of a series of substituted 5-aminopyrimidines and their potential prodrugs which may have implications in the treatment of oxidative stress-related diseases.     

Antimicrobial activity of some 2-aminopyrimidines

The minimum inhibitory concentration values for a group of pyrimidine derivatives were determined for Gram-positive and Gram-negative bacteria and yeast. The active compounds were further screened. The effect of these compounds on growth and morphology was tested, and their structural antimicrobial activity is discussed.     

Antibacterial activity of substituted 5-methylbenzo[c]phenanthridinium derivatives

Antibiotic resistance has prompted efforts to discover antibiotics with novel mechanisms of action. FtsZ is an essential protein for bacterial cell division, and has been viewed as an attractive target for the development of new antibiotics. Sanguinarine is a benzophenanthridine alkaloid that prevents cytokinesis in bacteria by inhibiting FtsZ self-assembly. In this study, a series of 5-methylbenzo[c]phenanthridinium derivatives were synthesized and evaluated for antibacterial activity against Staphylococcus aureus and Enterococcus faecalis. The data indicate that the presence of a 1- or 12-phenyl substituent on 2,3,8,9-tetramethoxy-5-methylbenzo[c]phenanthridinium chloride significantly enhances antibacterial activity relative to the parent compound or sanguinarine.     

Blood antioxidative enzymes during epileptic activity

It has been shown that the development of generalized epileptic activity in rats led to the decrease in superoxide dismutase (SOD) activity without affecting glutathione peroxidase (GP) and glutathione reductase (GR) activity. Long-term examination of 13 patients suffering from generalized forms of epilepsy has shown an about 30% decrease in SOD and GP activity in red blood cells. It is assumed that the functional insufficiency of the antioxidative system plays an essential role in the development of lipid peroxidation disturbances during epilepsy.     

New aminophosphonates with antioxidative activity.

The antioxidative activity of some newly synthesized aminomethanephosphonic acid derivatives was studied. The compounds studied differed in their polarity and the hydrophobicity of the electronic substituents at their nitrogen and phosphorus atoms. It was found that all the aminophosphonates studied, both cyclic and acyclic, protected erythrocyte membranes against peroxidation to some extent. The effect was somewhat weaker in the case of cyclic compounds, and for erythrocytes irradiated with UV light. The cyclic compounds provided no protection of erythrocytes illuminated by natural light. The observed differences between the antioxidative activities of cyclic and acyclic compounds are probably related to differences in their ability to incorporate into the lipid phase of erythrocyte membranes. Once incorporated, they change the fluidity of the membranes. The extent of those changes was determined in fluorescence measurements. Generally, they were found to be more pronounced in the case of acyclic aminophosphonates, although as regards other structural differences between particular aminophosphonates, a clear picture of the relationship between structure and effect is more difficult to obtain. No correlation was found between the antioxidative efficiency of the compounds and the fluidity changes they induce.     

The antioxidative activity of traditional Japanese herbs

The objective of this research was to examine the radical scavenging activity of traditional Japanese herbs. Samples used in the experiments were gennoshoko (Geranium nepalense var. thunbergii), yomogi (Artemisia vulgaris var.indica), senburi (Swertia japonica), iwa-tobacco (Conandron ramondioides), sarunokoshikake (Elfvingia applanata), kanzo (Glycyrrhiza uralensis Fisch) and matatabi (Actinidia polygama). The water-soluble components of the herbs were extracted in boiling water, and the volatile oil was extracted by a distillation apparatus or steeping in some organic solvents such as petroleum ether and ethyl ether. The radical scavenging activity was determined by the decrease of free radicals of DPPH detected by both colorimetric assay and HPLC method at 517 nm. The extracts of gennoshoko, yomogi and iwa-tobacco showed remarkable radical scavenging activity. The volatile oil of yomogi obtained by distillation or steeping in organic solvents had especially strong antioxidative activity.     

A method of determining the antioxidative activity of biological matter

A procedure is described for determining antioxidation activity of the water-soluble biological material. The procedure is based on the study of kinetics of the reduced 2.6-dichlorophenolindophenol oxidation by air oxygen both with and without the biological material as well as on calculation of the value for the constant of the biological material inhibition of 2.6-dichlorophenolindophenol oxidation as an index of the biological material antioxidation activity.     

Inhibition of the antioxidative activity of plasma by sodium azide

Powerful antioxidant activity of human plasma was demonstrated by measuring the thiobarbituric acid reaction and Fe+2-induced chemiluminescence. Inhibition of lipid peroxidation was shown both for plasma lipids and for the suspension of egg lipoproteins, which was taken as a model system. The inhibitory effect of plasma peroxidation was removed by azide Na taken in the concentration of 0.5 mg/ml, but caeroplasmin activity in the plasma was completely suppressed at NaN3 concentration equal to 0.1 mg/ml. A low correlation (r = 0.75) between caeruloplasmin activity in the blood plasma and extent of chemiluminescence activation obtained in the presence of NaN3 was found. The presented data led to an assumption that only a part of lipid peroxidation inhibitors in the plasma can be attributed with caeruloplasmin.     

Antifungal activity of substituted aurones

Novel antifungals are in high demand as there is a growing resistance to antifungals currently in use. In particular, opportunistic fungal infections caused by Candida spp. are on the rise with infections by this genus accounting for the most severe fungal infections following chemotherapy, implantation procedures, and in patients with HIV/AIDS. A series of simple aurone analogs were synthesized and screened for antifungal activity versus Candida spp. Several compounds displayed activity at 100 μM, with two having IC₅₀ values below 20 μM for three species of Candida. One of the compounds tested here also exhibits anti-biofilm activity for mid-maturation growth.     

Synthesis and antiviral activity of C-5 substituted beta-D- and beta-L-D4T analogues

A series of beta-D-2',3'-didehydro-2',3'-dideoxy-nucleosides bearing a tether attached at the C-5 position and their beta-L-counterparts was synthesized. Their inhibitory activities against human immunodeficiency virus (HIV) were investigated and compared to establish relationship(s) between compound structure and their antiviral activity. No significant activity was observed for beta-D- and beta-L-modified nucleosides respectively 7a-c and 14a-c, but 7d and 14d exhibited a weak activity against HIV-1.     

Antiviral activity of substituted 5-chlorodiphenylamine-2-carboxylic acid hydrazides and their N-benzylidene derivatives

The substituted 5-chlorodiphenylamine-2-carboxylic acid hydrazides and their N-benzylidene derivatives were tested for their antiviral activity against gomphrena mosaic virus in a hypersensitive hostin vitro as well asin vivo. Most of the compounds exhibited potential antiviral activity. These compounds may be useful in controlling viral infections in garden as well as in field crops.     

Amino substituted derivatives of 5'-amino-5'-deoxy-5'-noraristeromycin

The potent antiviral potential of 5'-amino-5'-deoxy-5'-noraristeromycin (2) is limited by associated toxicity. To seek derivatives of 2 that circumvent this undesirable property, three amino substituted derivatives (acetyl, 3; formyl, 4; and methyl, 5) of 2 have been prepared in 4-7 steps from the same intermediate, (1S,4R)-4-(6-chloropurin-9-yl)cyclopent-2-en-1-ol (6). Key steps involved an improved Pd(0)-catalyzed allylic azidation and a novel Pd(0)-catalyzed allylic amidation. The three target compounds were evaluated against a large number of viruses and found to be inactive except for a very weak effect of 5 on human cytomegalovirus, varicella zoster virus, and Epstein-Barr virus. There was also no noteworthy cytotoxicity associated with the new derivatives. Thus, these results indicate variation of the cyclopentyl amine of 2 does not offer a means to improve upon its antiviral potential.     

4-Aryl-5-cyano-2-aminopyrimidines as VEGF-R2 inhibitors: synthesis and biological evaluation

A novel series of 4-aryl-5-cyano-2-aminopyrimidines were synthesized and found to have potent VEGF-R2 kinase inhibitory activity. Structure-activity relationships were investigated and compound 14a was shown to be efficacious in a mouse model of corneal neovascularization.     

Catechol-based matrix metalloproteinase inhibitors with additional antioxidative activity

Abstract

New catechol-containing chemical entities have been investigated as matrix metalloproteinase inhibitors as well as antioxidant molecules. The combination of the two properties could represent a useful feature due to the potential application in all the pathological processes characterized by increased proteolytic activity and radical oxygen species (ROS) production, such as inflammation and photoaging. A series of catechol-based molecules were synthesized and tested for both proteolytic and oxidative inhibitory activity, and the detailed binding mode was assessed by crystal structure determination of the complex between a catechol derivative and the matrix metalloproteinase-8. Surprisingly, X-ray structure reveals that the catechol oxygens do not coordinates the zinc atom.     

Anti-influenza activity of monoterpene-containing substituted coumarins

Compounds simultaneously carrying the monoterpene and coumarin moieties have been tested for cytotoxicity and inhibition of activity against influenza virus A/California/07/09 (H1N1)pdm09. The structure of substituents in the coumarin framework, as well as the structure and the absolute configuration of the monoterpenoid moiety, are shown to significantly influence the anti-influenza activity and cytotoxicity of the compounds under study. The compounds with a bicyclic pinane framework exhibit the highest selectivity indices (the ratios between the cytotoxicity and the active dose). The derivative of (?)-myrtenol 15c, which is characterized by promising activity, low cytotoxicity, and synthetic accessibility, has the greatest potential among this group of compounds. It exhibited the highest activity when added to the infected cell culture at early stages of viral reproduction.     

Insecticidal activity of substituted phenyl N-methylcarbamates

The insecticidal and the acaricidal activities of a number of substituted phenyl N-methylcarbamates have been determined on the housefly (Musca domestica), the black bean aphid (Aphis fabae), the Colorado potato beetle (Leptinotarsa decemlineata), the cabbage worm (Pieris brassicae) and the carmine spider mite (Tetranychus cinnabarinus).It is demonstrated that the thesis of Kolbezen, Metcalf & Fukuto (1954), Metcalf, Fukuto & Winton (1962) and Kohn, Ospenson & Moore (1965), that the meta-isomers of alkylphenyl N-methylcarbamates are the most active, has to be restricted to some insect groups (e.g. flies and caterpillars). In the case of the Colorado potato beetle the o- and m-isomers were equally active; for aphids the o-isomer was the most toxic one.This fact as well as the different responses of the test insects if the compounds are further alkylated indicate that various carbamates exhibit more or less selective activities. Most striking was the high level of activity in the new group of p-dimethylaminomethylphenyl N-methylcarbamates on most of the insects, in combination with a complete lack of toxicity to houseflies.As previously pointed out by Kolbezen et al. (1954) and Metcalf et al. (1962), it was found that lengthening of the N-methyl group or N,N-dialkylation resulted in loss of insecticidal activity.The most active dimethylaminophenyl compounds were those with a p-dimethylamino group in combination with alkyl substituents in the 2,5- and 3,5-positions. Several p-dimethylaminomethylphenyl N-methylcarbamates with two or three alkyl substituents (except the 2,6-combination) proved to be highly active, except on flies, to which they were virtually nontoxic. Greatest broad-spectrum activity was shown by 2,3-dimethyl-4-dimethylaminomethylphenyl N-methylcarbamate. It is demonstrated that by introducing a p-dimethylamino- or a p-dimethylaminomethyl group in alkylphenyl N-methylcarbamates a considerable gain in anticholinesterase and insecticidal activity is obtained.

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Résumé p L'activité insecticide et acaricide de plusieurs N-méthylcarbamates de phényle substitués a été examinée sur la mouche domestique (Musca domestica), le puceron noir (Aphis fabae), le doryphore (Leptinotarsa decemlineata), la chenille de la piéride du chou (Pieris brassicae) et l'araignée rouge des serres (Tetranychus cinnabarinus). Les N-méthylcarbamates de phényle monosubstitués ne présentent qu'une faible activité acaricide. Les substances avec des substitutions en position méta ou ortho montrent une meilleure activité insecticide que celles avec la substitution en position para. Pour les mouches domestiques l'alcoylation en position méta se trouve donner les composés les plus actifs; pour les pucerons l'alcoylation en position ortho était la plus efficace et pour les doryphores les combinaisons o- et m-étaient d'une activité égale. Les isomères ortho des dérivés alcoxylés étaient plus efficaces. En cas de substitution par un groupe diméthylamino il n'y a pas de différence importante quant à l'activité insecticide entre les positions ortho ou méta. En général il en est de même pour les substitutions par diméthylaminométhyle, bien que le m-isomère soit le plus efficace sur les chenilles.L'introduction d'un deuxième groupe alcoyle dans un N-méthylcarbamate de o- ou m-isopropylphényle change le spectre d'action. Un groupe 5-méthyle diminue beaucoup l'activité de l'o-isomère. Un groupe 5-isopropyle diminue l'activité sur les pucerons, mais pas sur les mouches. Quand un groupe 5-méthyle ou 5-isopropyle est introduit dans un N-méthylcarbamate de m-isopropyl-phényle l'activité est généralement augmentée. L'introduction d'un groupe 6-méthyle diminue toutefois l'activité sur les mouches, les pucerons et les chenilles, mais pas sur les Coléoptères et les araignées rouges.Les N-méthylcarbamates de phényle s'avèrent posséder une meilleure activité que les combinaisons N,N-diméthylcarbamates correspondantes. Une prolongation du groupe N-alcoyle diminue également l'activité.Les dérivés de N-méthylcarbamates de 2-diméthylamino-phényle ont une plus grande activité que les isomères méta correspondants. On trouve toutefois la meilleure activité dans les N-méthylcarbamates de 4-diméthylamino-phényle alcoylés. Tout groupe alcoyle, à condition d'être introduit en position 2-, 3-, ou 5-augmente l'activité insecticide. Les composés métasubstitués semblent encore un peu plus actifs que les dérivés d'o-alcoyle. La grande activité sur les pucerons contraste nettement avec la faible activité sur les mouches et les araignées rouges. Le seul dérivé présentant une bonne activité sur les araignées rouges est le N-méthylcarbamate de 3-isopropyl-4-diméthylamino-5-méthylphényle.Les N-méthylcarbamates de p-diméthylaminométhyl-phényle alcoylés présentent également une forte action insecticide, sauf sur les mouches. Le N-méthylcarbamate de 2, 3-diméthyl-4-diméthylaminométhyl-phényle présente la plus grande activité et le plus large spectre d'action.A partir des N-méthylcarbamates d'alcoylphényle l'introduction d'un groupe p-diméthylamino ou p-diméthylamino-méthyle augmente considérablement l'activité anticholinestérasique aussi bien que l'activité insecticide.

     

Synthesis, cytostatic activity and ADME properties of C-5 substituted and N-acyclic pyrimidine derivatives

The synthesis of the novel 5-alkyl pyrimidine derivatives, 5,6-dihydrofuro[2,3-d]pyrimidines and 5-alkyl N-methoxymethyl pyrimidine derivatives and evaluation of their cytostatic activities are described. The mechanism of antiproliferative effect of 5-(2-chloroethyl)-substituted pyrimidine 3 that exerted the pronounced cytostatic activity was studied in further details on colon carcinoma (HCT116) cells. The cell cycle perturbation analysis demonstrated severe DNA damage (G2/M arrest) pointing to a potential DNA alkylating ability of 3. Preliminary ADME data of 3 and its 6-methylated structural congener (6-Me-3) showed their high permeability and good metabolic stability.